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Afatinib—an oral irreversible ErbB family blocker—improves progression-free survival compared with pemetrexed and cisplatin for first-line treatment of patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). We compared afatinib with gemcitabine and cisplatin—a chemotherapy regimen widely used in Asia—for first-line treatment of Asian patients with EGFR mutation-positive advanced NSCLC. This open-label, randomised phase 3 trial was done at 36 centres in China, Thailand, and South Korea. After central testing for EGFR mutations, treatment-naive patients (stage IIIB or IV cancer [American Joint Committee on Cancer version 6], performance status 0–1) were randomly assigned (2:1) to receive either oral afatinib (40 mg per day) or intravenous gemcitabine 1000 mg/m2 on day 1 and day 8 plus cisplatin 75 mg/m2 on day 1 of a 3-week schedule for up to six cycles. Randomisation was done centrally with a random number-generating system and an interactive internet and voice-response system. Randomisation was stratified by EGFR mutation (Leu858Arg, exon 19 deletions, or other; block size three). Clinicians and patients were not masked to treatment assignment, but the independent central imaging review group were. Treatment continued until disease progression, intolerable toxic effects, or withdrawal of consent. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). This study is registered with ClinicalTrials.gov, NCT01121393. 910 patients were screened and 364 were randomly assigned (242 to afatinib, 122 to gemcitabine and cisplatin). Median progression-free survival was significantly longer in the afatinib group (11·0 months, 95% CI 9·7–13·7) than in the gemcitabine and cisplatin group (5·6 months, 5·1–6·7; hazard ratio 0·28, 95% CI 0·20–0·39; p<0·0001). The most common treatment-related grade 3 or 4 adverse events in the afatinib group were rash or acne (35 [14·6%] of 239 patients), diarrhoea (13 [5·4%]), and stomatitis or mucositis (13 [5·4%]), compared with neutropenia (30 [26·5%] of 113 patients), vomiting (22 [19·5%]), and leucopenia (17 [15·0%]) in the gemcitabine and cisplatin group. Treatment-related serious adverse events occurred in 15 (6·3%) patients in the afatinib group and nine (8·0%) patients in the gemcitabine and cisplatin group. First-line afatinib significantly improves progression-free survival with a tolerable and manageable safety profile in Asian patients with EGFR mutation-positive advanced lung NSCLC. Afatinib should be considered as a first-line treatment option for this patient population. Boehringer Ingelheim.

Depression is common in patients with Parkinson's disease, but evidence on the efficacy of antidepressants in this population is lacking. Because depression in patients with Parkinson's disease might be related to dopaminergic dysfunction, we aimed to assess the efficacy of the dopamine agonist pramipexole for treatment of depressive symptoms in patients with Parkinson's disease. We did a 12-week randomised, double-blind, placebo-controlled (1:1 ratio) trial of pramipexole (0·125–1·0 mg three times per day) compared with placebo in patients with mild-to-moderate Parkinson's disease. Patients from 76 centres in 12 European countries and South Africa were included if they were on stable antiparkinsonian therapy without motor fluctuations and had depressive symptoms (15-item geriatric depression scale score ≥5 and unified Parkinson's disease rating scale [UPDRS] part 1 depression item score ≥2). Patients were randomly assigned by centre in blocks of four by use of a randomisation number generating system. Clinical monitors, the principal investigator, and patients were masked to treatment allocation. The primary endpoint was change in Beck depression inventory (BDI) score and all treated patients who had at least one post-baseline efficacy assessment were included in the primary analysis. We also did a pre-specified path analysis with regression models to assess the relation between BDI and UPDRS part 3 (motor score) changes. This trial is registered with ClinicalTrials.gov, number NCT00297778, and EudraCT, number 2005-003788-22. Between March, 2006, and February, 2008, we enrolled 323 patients. Of 296 patients randomly assigned to pramipexole or placebo, 287 were included in the primary analysis: 139 in the pramipexole group and 148 in the placebo group. BDI scores decreased by an adjusted mean 5·9 (SE 0·5) points in the pramipexole group and 4·0 (0·5) points in the placebo group (difference 1·9, 95% CI 0·5–3·4; p=0·01, ANCOVA). The UPDRS motor score decreased by an adjusted mean 4·4 (0·6) points in the pramipexole group and 2·2 (0·5) points in the placebo group (difference 2·2, 95% CI 0·7–3·7; p=0·003, ANCOVA). Path analysis showed the direct effect of pramipexole on depressive symptoms accounted for 80% of total treatment effect (p=0·04). Adverse events were reported in 105 of 144 patients in the pramipexole group and 101 of 152 in the placebo group. Adverse events in the pramipexole group were consistent with the known safety profile of the drug. Pramipexole improved depressive symptoms in patients with Parkinson's disease, mainly through a direct antidepressant effect. This effect should be considered in the clinical management of patients with Parkinson's disease. Boehringer Ingelheim.

The role of gut microbiomes as important regulators of mammalian health is increasingly recognized, although feline and canine gut microbiomes remain poorly characterized. In this proof-of-concept study, we assessed the utility of a direct-to-consumer approach to executing pet microbiome studies. We characterized the gut microbiomes of 238 pets (46 cats and 192 dogs) by generating ~11 million merged reads that were mapped to the V4 region of 16S ribosomal RNA gene at a sequencing depth of 45,806 (±22,325) reads per sample. Analyses of these reads revealed that both feline and canine gut microbiomes are dominated by three major phyla, namely Firmicutes, Proteobacteria, and Bacteroides and that alpha diversity is higher in the feline gut. In addition to interspecies differences between the feline and canine gut, we also detected appreciable intraspecies bacterial variation within the canine population. While the dogs in this dataset could be assigned to three distinct clusters based on their gut microbiome, no clustering was observed within the feline population. Integration of additional data obtained from survey questionnaires revealed that geography and body weight may be associated with canine gut microbiome composition. Furthermore, we found that both the inter and intraspecies differences are more pronounced at finer taxonomic levels, indicating that strain-level investigations may be necessary in the future. This study demonstrates that the direct-to-consumer approach overcomes existing limitations in pet microbiome research, for example, it allows collection of large numbers of pet samples. The direct-to-consumer approach has proven successful in human genomics as well as human microbiomics and this study demonstrates that by building partnerships with an engaged general public this approach can also propel the field of pet microbiomics forward.

In LUX‐Lung 3, afatinib significantly improved progression‐free survival (PFS) versus cisplatin/pemetrexed in EGFR mutation‐positive lung adenocarcinoma patients and overall survival (OS) in Del19 patients. Preplanned analyses in Japanese patients from LUX‐Lung 3 were performed. Patients were randomized 2:1 to afatinib or cisplatin/pemetrexed, stratified by mutation type (Del19/L858R/Other). Primary endpoint was PFS (independent review). Secondary endpoints included OS, objective response, and safety. Median PFS (data cut‐off: February 2012) for afatinib versus cisplatin/pemetrexed was 13.8 vs 6.9 months (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.20–0.70; P = 0.0014) in all Japanese patients (N = 83), with more pronounced improvements in those with common mutations (Del19/L858R; HR, 0.28; 95% CI, 0.15–0.52; P < 0.0001) and Del19 mutations (HR, 0.16; 95% CI, 0.06–0.39; P < 0.0001). PFS was also improved in L858R patients (HR, 0.50; 95% CI, 0.20–1.25; P = 0.1309). Median OS (data cut‐off: November 2013) with afatinib versus cisplatin/pemetrexed was 46.9 vs 35.8 months (HR, 0.75; 95% CI, 0.40–1.43; P = 0.3791) in all Japanese patients, with greater benefit in patients with common mutations (HR, 0.57; 95% CI, 0.29–1.12; P = 0.0966) and Del19 mutations (HR, 0.34; 95% CI, 0.13–0.87; P = 0.0181); OS was not significantly different in L858R patients (HR, 1.13; 95% CI, 0.40–3.21; P = 0.8212). Following study treatment discontinuation, most patients (93.5%) received subsequent anticancer therapy. The most common treatment‐related adverse events were diarrhea, rash/acne, nail effects and stomatitis with afatinib and nausea, decreased appetite, neutropenia, and leukopenia with cisplatin/pemetrexed. Afatinib significantly improved PFS versus cisplatin/pemetrexed in Japanese EGFR mutation‐positive lung adenocarcinoma patients and OS in Del19 but not L858R patients (www.clinicaltrials.gov; NCT00949650). In subgroup analyses of LUX‐Lung 3, afatinib significantly improved progression‐free survival versus cisplatin/pemetrexed in Japanese patients with EGFR mutation‐positive lung adenocarcinoma. Overall survival was significantly improved with afatinib in Japanese patients with Del19 mutation, while overall survival in Japanese patients with L858R mutation was similar between treatment arms.

Background: In the Phase III LUX-Lung 3/6 (LL3/LL6) trials in epidermal growth factor receptor ( EGFR ) mutation-positive lung adenocarcinoma patients, we evaluated feasibility of EGFR mutation detection using circulating cell-free DNA (cfDNA) and prognostic and predictive utility of cfDNA positivity (cfDNA+). Methods: Paired tumour and blood samples were prospectively collected from randomised patients. Mutations were detected using cfDNA from serum (LL3) or plasma (LL6) by a validated allele-specific quantitative real-time PCR kit. Results: EGFR mutation detection rates in cfDNA were 28.6% (serum) and 60.5% (plasma). Mutation detection in blood was associated with advanced disease characteristics, including higher performance score, number of metastatic sites and bone/liver metastases, and poorer prognosis. In patients with common EGFR mutations, afatinib improved progression-free survival vs chemotherapy in cfDNA+ (LL3: HR, 0.35; P =0.0009; LL6: HR, 0.25; P <0.0001) and cfDNA− (LL3: HR, 0.46; P <0.0001; LL6: HR, 0.12; P <0.0001) cohorts. A trend towards overall survival benefit with afatinib was observed in cfDNA+ patients. Conclusions: Plasma cfDNA is a promising alternative to biopsy for EGFR testing. Detectable mutation in blood was associated with more advanced disease and poorer prognosis. Afatinib improved outcomes in EGFR mutation-positive patients regardless of blood mutation status.

Background Xentuzumab is a humanised monoclonal antibody that binds to IGF-1 and IGF-2, neutralising their proliferative activity and restoring inhibition of AKT by everolimus. This study evaluated the addition of xentuzumab to everolimus and exemestane in patients with advanced breast cancer with non-visceral disease. Methods This double-blind, randomised, Phase II study was undertaken in female patients with hormone-receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative advanced breast cancer with non-visceral disease who had received prior endocrine therapy with or without CDK4/6 inhibitors. Patients received a weekly intravenous infusion of xentuzumab (1000 mg) or placebo in combination with everolimus (10 mg/day orally) and exemestane (25 mg/day orally). The primary endpoint was progression-free survival (PFS) per independent review. Results A total of 103 patients were randomised and 101 were treated (n = 50 in the xentuzumab arm and n = 51 in the placebo arm). The trial was unblinded early due to high rates of discordance between independent and investigator assessment of PFS. Per independent assessment, median PFS was 12.7 (95% CI 6.8–29.3) months with xentuzumab and 11.0 (7.7–19.5) months with placebo (hazard ratio 1.19; 95% CI 0.55–2.59; p = 0.6534). Per investigator assessment, median PFS was 7.4 (6.8–9.7) months with xentuzumab and 9.2 (5.6–14.4) months with placebo (hazard ratio 1.23; 95% CI 0.69–2.20; p = 0.4800). Tolerability was similar between the arms, with diarrhoea (33.3–56.0%), fatigue (33.3–44.0%) and headache (21.6–40.0%) being the most common treatment-emergent adverse events. The incidence of grade ≥ 3 hyperglycaemia was similar between the xentuzumab (2.0%) and placebo (5.9%) arms. Conclusions While this study demonstrated that xentuzumab could be safely combined with everolimus and exemestane in patients with HR-positive/HER2-negative advanced breast cancer with non-visceral disease, there was no PFS benefit with the addition of xentuzumab. Trial registration ClinicalTrials.gov, NCT03659136. Prospectively registered, September 6, 2018.

Background EMPA–KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. Methods Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20 < 45; or ≥ 45 < 90 ml/min/1.73m 2 with a urinary albumin-to-creatinine ratio (uACR) of ≥ 200 mg/g. The primary outcome was a composite of kidney disease progression (end-stage kidney disease, a sustained eGFR decline to < 10 ml/min/1.73m 2 or ≥ 40% from randomization, or renal death) or cardiovascular death. In post-hoc analyses, we explored the effects of empagliflozin in participants from Japan vs. non-Japan regions, including additional models assessing whether differences in treatment effects between these regions could result from differences in baseline characteristics. Results Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64–0.82; P  < 0.0001). Among the participants from non-Japan regions, there were 399 vs. 494 primary outcomes (0.75, 0.66–0.86), and 33 vs. 64 (0.49, 0.32–0.75; heterogeneity p  = 0.06) in Japan. Results were similar when models explicitly considered treatment interactions with diabetes status, categories of eGFR/uACR, and recruitment in Japan (heterogeneity p  = 0.08). Safety outcomes were broadly comparable between the two groups, and by Japanese status. Conclusions Empagliflozin safely reduced the risk of “kidney disease progression or cardiovascular death” in patients with CKD, with consistent effects in participants from Japan.

The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3–33·9). Progression-free survival (median 11·0 months [95% CI 10·6–12·9] with afatinib vs 10·9 months [9·1–11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57–0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9–15·0] with afatinib vs 11·5 months [10·1–13·1] with gefitinib; HR 0·73 [95% CI 0·58–0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. Boehringer Ingelheim.

PurposeIn the randomized phase IIb LUX-Lung 7 trial, afatinib significantly improved progression-free survival (PFS) and time-to-treatment failure vs gefitinib in patients with treatment-naïve epidermal growth factor receptor mutation-positive non-small cell lung cancer. We report post hoc analyses of tolerability-guided dose adjustment for afatinib and summarize the clinical characteristics of patients who continued afatinib/gefitinib beyond initial radiological progression in LUX-Lung 7.MethodsPatients received afatinib 40 mg/day or gefitinib 250 mg/day until investigator-assessed progression or beyond if beneficial. In case of selected treatment-related adverse events (TRAEs), the afatinib dose could be reduced by 10-mg decrements to minimum 20 mg (only dose interruptions were permitted with gefitinib).ResultsAll randomized patients were treated (afatinib, n = 160; gefitinib, n = 159). Sixty-three patients had afatinib dose reduction (< 40 mg/day; 47 within first 6 months). Dose reduction decreased TRAE incidence/severity (before vs after; all grade/grade 3: 100.0%/63.5% vs 90.5%/23.8%). There was no evidence of significant difference in PFS for patients who received < 40 mg/day vs ≥ 40 mg/day for the first 6 months [median: 12.8 vs 11.0 months; hazard ratio 1.34 (95% confidence interval 0.90–2.00)]. Twenty-four and 26 patients continued afatinib and gefitinib, respectively, beyond progression in target lesions; median time from nadir of target lesion diameters to initial progression was 6.7 months and 5.6 months. Of these patients, ~ 70% had objective response or non-complete response/non-progressive disease in non-target lesions at initial progression.ConclusionsProtocol-defined dose adjustment of afatinib may allow patients to remain on treatment longer, maximizing clinical benefit even in the presence of radiological progression.

The DNS Security Extensions (DNSSEC) are among the first attempts to deploy cryptographic protections in an Internet-scale operational system. DNSSEC applies well-established public key cryptography to ensure data integrity and origin authenticity in the DNS system. While the cryptographic design of DNSSEC is sound and seemingly simple, its development has taken the IETF over a decade and several protocol revisions, and even today its deployment is still in the early stage of rolling out. In this paper, we provide the first systematic examination of the design, deployment, and operational challenges encountered by DNSSEC over the years. Our study reveals a fundamental gap between cryptographic designs and operational Internet systems. To be deployed in the global Internet, a cryptographic protocol must possess several critical properties including scalability, flexibility, incremental deployability, and ability to function in face of imperfect operations. We believe that the insights gained from this study can offer valuable inputs to future cryptographic designs for other Internet-scale systems.